Exploration of facilitators and barriers to the regulatory frameworks of dietary and herbal supplements: a scoping review

Background Over the last decade, the use of dietary and herbal supplements (DHSs) has expanded greatly across national healthcare settings for the prevention, management and/or treatment of a variety of health issues. Although regulatory policies for DHSs across different countries have been aimed towards evaluating safety and efficacy, performing quality controls, monitoring the manufacturing practices, and encouraging further research, significant safety issues have emerged from inappropriate regulatory classification, lack of suitable quality controls, and inadequate testing and labeling of these products. Therefore, the purpose of this scoping review was to identify facilitators and barriers to DHS regulation across different countries. Methods A scoping review was conducted and informed by the five-stage methodological framework proposed by Arksey and O’Malley and further enhanced by Levac et al. MEDLINE, EMBASE, AMED, and PsycINFO databases were systematically searched for eligible articles from database inception to September 29, 2020. Studies analyzing DHS regulatory frameworks were eligible for review. Relevant data from eligible articles were extracted and categorized into themes to provide a descriptive overview of the literature. Results Searches generated 4314 results, 1800 of which were duplicates, followed by 2472 that were excluded after screening the titles and abstracts of these articles. Of the remaining 42 full-texts, 15 eligible articles were included in this review. Themes identified include: (1) increased financial and human resources encouraging knowledge expansion as a facilitator to DHS regulation; (2) variances in DHS classification and regulatory requirements across countries as a barrier to DHS regulation, and (3) collaboration between various stakeholders (experts, policymakers, representatives of regulatory bodies, product companies and research institutions) facilitating DHS regulation. Conclusion The present scoping review identified facilitators and barriers to DHS regulation across different countries. We highlight that safety assessments of DHSs continue to be inadequate, and emerging technologies could potentially play a significant role in establishing common reference standards of herbal materials and products between regulatory agencies. Regulatory harmonization, increased scientific research, and collaboration could improve regulations globally through appropriate categorization and safe application of DHSs.


Background
Over 80% of the global population relies on dietary and herbal supplements (DHSs) to supplement their healthcare needs and prevent common ailments [1,2]. DHSs include vitamins and minerals, herbal supplements, enzymes, amino acids, and tissue from organs or glands [3]. They are marketed in various forms such as tablets, powders, and tinctures, and are used for a variety of reasons such as to supplement diets, help with medical conditions, boost energy, or improve quality of sleep [4]. Similarly, herbal supplements contain one or more herbs that can be any form of a plant or plant product to improve overall health [3,5].
There are different terms used in reference to DHSs across the literature, including natural health products (NHPs), herbal medicines (HMs), and indigenous natural products (INPs), which can be used in traditional and complementary medicine (T&CM) systems, such as traditional Chinese medicine (TCM). We refer to these terms as DHSs for the purpose of this review, but acknowledge that there are inherent differences between these terms and their regulations within a specific jurisdiction and that these products may overlap across categories between different countries. Therefore, it is important to define these variances between international categorizations: NHPs, like DHSs, include vitamins and mineral supplements, homeopathic medicines, herbal therapies, and also comprise other traditional medicines subclasses such as Ayurveda, and Native North American medicines [6]; traditional medicine is a system based on the knowledge, skills, and practices belonging to different cultures that may include the use of DHSs for the maintenance of health [7]; HMs are one type of dietary supplement obtained from vegetable, fungal or algae sources as active raw materials with therapeutic or other human health benefits [7]; TCM includes DHSs as a subset of herbal remedies and pharmacologically active substances grown throughout China, but it also includes acupuncture, moxibustion, massage, food therapy, and physical exercise [8]; INPs grown in Southern Africa are categorized as herbs and botanicals (a modality of DHSs) and mainly comprise plant products containing active herbal components that can be used as ingredients in medicinal preparations [9].
The general perception of DHSs being safe because they are more "natural" when compared to prescription medications is often misleading, as some DHSs have been shown to cause various adverse reactions, some of which may result in serious injuries and lifethreatening conditions [1,[10][11][12][13]. Significant safety issues have also resulted from inappropriate regulatory classifications, a lack of suitable quality controls, and inadequate testing and labeling of these products. For example, countries that classify traditional and HM as foods or dietary supplements do not require evidence of safety and efficacy before being marketed or require fewer rigorous product quality tests [1]. In the case of the United States, products directly classified under the dietary supplement pathway are not fully assessed before marketing, whereas products categorized as botanical drugs often require stricter scientific evaluation by the government prior to advertising, selling, and/or delivering DHSs to consumers [3,14]. On the other hand, in Canada, DHSs are referred to as NHPs, and the registration procedure of DHSs is regulated by the Natural and Non-Prescription Health Product Directorate, a branch of Health Canada [15]. NHPs are licensed through two different pathways: (1) NHPs making modern health claims or (2) NHPs claiming to be used as traditional medicines [15].
The nature of regulatory policies for DHSs across different countries has been aimed towards evaluating their safety and efficacy, performing quality controls of the raw materials used, monitoring the manufacturing practices, and encouraging more research to expand DHS knowledge within national drug authorities [10,16,17]. For example, the Therapeutic Goods Association of the Australian government established a pharmacovigilance program to assess adverse events reported by complementary medicine consumers, healthcare professionals, and international medical and scientific experts on advisory boards [16]. When compared to countries such as France, Brazil, and Austria, that have established laws regarding DHS registration, Kuwait and Bahrain lack a well-defined regulatory system as they primarily import DHSs from other countries [18]. Moreover, in the United Kingdom, many unlicensed herbal remedies reached consumers without meeting safety or quality standards until 2010 [19]. Subsequently, in 2011, the European Union established a simplified licensing system requiring a product license on all HMs to validate product efficacy, safety, and quality, before being manufactured [19,20]. To our knowledge, a research gap exists due to the fact that no study has yet systematically identified and summarized research which evaluates the facilitators and barriers to DHS regulation in a global context, thus making this the purpose of the present review. Ng et al. Journal of Pharmaceutical Policy and Practice (2022) 15:55 Methods Approach A scoping review was conducted to identify the facilitators and barriers to DHS regulation. It was informed by Arksey and O'Malley's five-stage scoping review framework and further enhanced by Levac et al. [21,22]. The methodology consists of five stages: (1) identifying the research question, (2) identifying relevant studies, (3) selecting the studies, (4) charting the data, and (5) collating, summarizing, and reporting the results. This method required searching for and assessing the available literature on a given topic to identify the characteristics of eligible articles, summarize their contents, and highlight knowledge gaps.

Step 1: identifying the research question
The research question was as follows: What barriers and facilitators to the regulation of DHSs can be identified by studies evaluating policies and regulatory frameworks across different countries? For this study, we defined a "facilitator" as any factor that allows or promotes the implementation of DHS regulations. We defined a "barrier" as any factor that prevents or hinders the implementation of DHS regulations.

Step 2: finding relevant studies
Following a preliminary scan of the literature, we conducted systematic searches on MEDLINE, EMBASE, AMED, and PsycINFO on September 30, 2020 from database inception until September 29, 2020. The search strategy (Table 1) included indexed headings and terms used in the literature to refer to DHS regulation. The reference lists of relevant reviews were also searched for any additional eligible studies.
Step 3: selecting the studies Preliminary searches indicated that evaluative studies have been conducted within this subject area, albeit the volume of literature appeared sparse. We only included articles that discussed the DHS framework of one or more countries. For studies evaluating the regulation of non-DHSs, MK and AS examined what products were in question. The studies were deemed eligible if information pertaining to at least one ingredient of DHSs was discussed. While reviews themselves were excluded, we hand-searched their reference lists for eligible articles. All other types of articles such as commentaries, editorials, or conference abstracts were ineligible. Studies that exclusively evaluated regulatory frameworks of non-DHSs (i.e., complementary and alternative medicines such as acupuncture or chiropractic) were excluded. Studies exclusively evaluating the regulatory framework surrounding cannabis were also excluded as it is commonly regulated separately from DHSs; this work is instead presented in a separate review [23]. All retrieved articles were pilot-screened for eligibility by MK and AS independently and in duplicate, based on the title and abstract, followed by the screening of the full-texts of the articles. After every round of independent screening, all three authors met to discuss and resolve any conflicts or discrepancies.
Step 4: charting the data Articles that met the inclusion criteria were critically reviewed using the descriptive-analytical narrative method. The following items from each eligible article were extracted and charted: first author and year; article title; the country where the study was conducted; the  15:55 countries discussed in the article in relation to DHS regulation; study aim; conclusion; participants or document type/level of policy-making; types of evidence; summary of description of methods; facilitators to the implementation of DHS regulations; and barriers to the implementation of DHS regulations. Data extraction was conducted independently and in duplicate by MK and AS. Following this, all three authors met to discuss and resolve any discrepancies.
Step 5: collating, summarizing, and reporting the results All eligible articles were reviewed by MK and AS. Data were then analyzed and organized in a tabular format to provide a descriptive overview of emerging and prevalent themes across the literature. This descriptive data were then categorized into distinct themes by MK and AS. JYN identified commonalities between themes and organized them under overarching thematic categories, and all authors subsequently presented the findings under each corresponding theme.

Results
Searches generated 4314 results, 1800 of which were removed as duplicates. Of the remaining items, 2472 were excluded based on title/abstract screening, leaving 42 full-text articles to be further reviewed. Of these, 27 articles were deemed ineligible because they did not evaluate the facilitators and/or barriers to DHS regulation (n = 21), were irretrievable (n = 3), were review articles (n = 2), or was a conference abstract (n = 1), resulting in a total of 15 eligible articles that were included in this scoping review. A PRISMA diagram can be found in Fig. 1.

Eligible article characteristics
Eligible articles were published between 2001 and 2019, and were conducted in Brazil (n = 4), Canada (n = 4), India (n = 1), Lebanon (n = 1), Namibia (n = 1), Nigeria (n = 1), and the United Kingdom (n = 1). Additionally, one study originated from both the United States and Ghana, and another study originated from both Bahrain and Kuwait. The 15 eligible studies had various aims ranging from evaluating current international DHS regulations to assessing propositions of new regulatory frameworks. Additionally, interviews (n = 7) and surveys (n = 5) were the most common methods utilized to gather qualitative data about the current regulatory framework of DHSs in each country and to explore the different perspectives of stakeholders involved. Comprehensive details of the eligible articles can be found in Table 2. Additionally, a detailed summary of policy-making levels and the facilitators and barriers to DHS regulations is located in Table 3.

Finding from thematic analysis
The regulation of DHSs was explored through the following themes representing a facilitator or barrier to DHS regulation: (1) increased financial and human resources encouraging knowledge expansion as a facilitator to DHS regulation; (2) variances in DHS classification and regulatory requirements across countries as a barrier to DHS regulation; and (3) collaboration between various stakeholders (experts, policymakers, representatives of regulatory bodies, product companies and research institutions) facilitating DHS regulation.

Theme 1: increased financial and human resources encouraging knowledge expansion as a facilitator to DHS regulation
Financial initiatives to encourage research on DHSs have positively impacted their regulation in eight countries, especially with new regulatory frameworks now requiring rigorous scientific testing and sufficient research data before the registration and marketing of these products [24]. HM researchers in Ghana did not have adequate funding to conduct clinical trials and measure safety and efficacy of HMs. Due to the lack of trial data, they struggled to register herbal supplements for marketing [25]. Conversely, in Brazil, the National Policy on Medicinal Plants and Herbal Medicine has encouraged research in medicinal plants through financial incentive programs organized by the Ministry of Health and other governmental agencies, such as the National Committee of Medicinal Plants and Herbal Medicines, that work to support the harmonization of the Brazilian market. Regulatory authorities are then able to refer to one unique set of information on a herbal substance when evaluating marketing applications for HMs [26]. It was also noted that more than 58% of herbal medicine research programs were established solely due to incentives offered by local authorities and the federal government of Brazil [26]. Similarly, the government of India has organized exhibitions to promote knowledge exchange between scholars in the field of HM and provided technical and financial support to universities and institutions specializing in HM research [24]. The government's establishment of the Indo-US Centre for Research on Indian Systems of Medicine has also promoted collaboration on research between traditional medicine and Ayurveda practitioners in India and HM researchers in the United States. Encouraging this integration of evidencebased traditional medicine methodologies from the United States with traditional herbal medicine systems, such as Ayurveda, Siddha, and Unani, in India has led to the development of training workshops involving both countries [24]. Moreover, evidence-based submissions of safety and efficacy studies on herbal supplements in India have become increasingly important for receiving marketing approval, and as such, there has been an increasing necessity to focus on scientific and technological advances within the field of HM [24]. Therefore, the implementation of such programs helped to ensure that India acquired adequate scientific approval of its HM frameworks in other countries [24]. In addition to research, there has been a need for greater financial support to hire sufficient staff and train them to implement HM policies. The National Health Regulatory Authority of Bahrain, for example, has benefited from its high number of scientific reviewers due to their familiarity with policy implementation, which does not require additional training. This abundance of reviewers also facilitated the rapid implementation of HM classification guidelines [18]. On the other hand, Kuwait's lack of properly trained reviewers and severe staff shortages has prompted several key officials from its drug regulatory authorities to propose an increase in the number of reviewers involved in the HM registration process, including herbal specialists who are knowledgeable in HM science, in order to resolve any confusions that may arise in policy-making discussions [18]   Furthermore, it seems that many HMs escape a comprehensive review and are rather portrayed as dietary supplements in some areas across the globe. This is a matter of concern when establishing registration policies in Kuwait, which usually imports such products and aims to evaluate these considering their governing context in their native country.
Appiah et al. 2018 [25] Identifying strengths and weaknesses of the integration of biomedical and herbal medicine units   Walji et al. 2013 [29] Governance of natural health products regulation: an iterative process Canada Canada To understand the contextual factors and major challenges involved in implementing regulation of NHPs in Canada. Health Canada's experience with implementing regulation of NHPs highlights several challenges including time to process applications, issues with defining the products and labeling. However, there is a need to monitor and survey any adverse effects in both passive and active manner.
Alameddine et al. 2011 [27] Stakeholders' perspectives on  officials lacked a central, federally run laboratory to conduct robust safety and efficacy testing before complementary and alternative medicine products were introduced to the market because they do not have adequate human resources at their Ministry of Health headquarters. As a result, the current regulatory body has struggled to efficiently regulate complementary and alternative medicine products effectively without the adequate expertise available to analyze and monitor them [27].

Theme 2: variances in DHS classification and regulatory requirements across countries as a barrier to DHS regulation
The differences in classification and existing regulations of DHS products have caused ambiguities, making it difficult to develop and implement regulatory policies. For instance, Brazilian policymakers and government officials have been unable to homogenize the definition of HM across international drug regulatory authorities and thus lacked clarity when deciding under which category to register the products. This allowed different HMs with the same active ingredients and characteristics to be registered in more than one department, creating inconsistencies and duplications in product registration [18]. The Kuwait Drug and Food Control and Authority regulatory system allocates HM supplements under the "Herbal", the "Dietary Supplement", or the "Unclassified" departments based on their composition; however, the absence of clear classification guidelines has led to inconsistent registration of different HM products with identical active ingredients [28]. Additionally, HMs that were registered under the unclassified unit as dietary supplements or as functional food under the food supplements unit required fewer and less stringent requirements for registration, and thus inappropriately circumvented rigorous safety and efficacy evaluations. Since Kuwait has frequently imported HMs from the United Kingdom, Germany, the United States, the United Arab Emirates, and the Kingdom of Bahrain, variances in herbal supplement categorizations have made it difficult for the Kuwait Drug and Food Administration to adopt existing classifications into their drug regulatory authority system and subsequently regulate the same products in their own country [28]. Therefore, a standardized definition may help to ensure that all HMs imported from other countries undergo the most appropriate conformity assessment before entering the Kuwaiti market to become regulated under one of five separate registration units (pharmaceutical, herbal, veterinary, unclassified, cosmetics and food supplements unit) [28].
Differences in regulatory requirements between herbal medicine approval procedures and submission requirements of India, the United States, and the European Union have presented consumer risks. Under the Drug and Cosmetics Act of 1940 in India, for instance, traditional HMs with a long history of use are assumed to be safe, and thus safety or efficacy data on their products is not necessary for marketing approval. Indian manufacturers have sold the majority of these HM products in the United States as dietary supplements because they do not require approval prior to producing or selling DHSs, and such categorization does not require scientific evidence of safety nor efficacy under the Dietary Supplement Health and Education Act of 1994 [24]. This has led to subsequent delays in Indian HM application processes requiring preclinical safety data (including toxicologic and pharmacologic test data) due to the lack of pharmacopeia harmonization that would better support the registration of drugs including HMs across countries. For example, manufacturers in the United States have struggled to market their HM products in India because unlike the United States Pharmacopoeia, the Indian Pharmacopoeia does not have a separate category for dietary supplements. As a result, government regulators who review drug applications are constantly faced with the challenge of the lack of consistency with pharmacopeia standards across different countries [24]. Small and mediumsized manufacturers also faced commercialization issues as they were burdened with the need to perform product analyses based on different acceptance criteria in order to satisfy pharmacopoeial requirements that vary across regions. Therefore, standardization of accepted quality parameters for HM products and ingredients could aid in providing standards for their quality control [24].
In Canada, NHPs were not previously categorized distinctly from food and drugs, resulting in confusion surrounding where certain products should fit. Having NHPs classified as a separate category has facilitated the implementation of regulations, which have since been continuously revised [29,30]. Overall, the adoption of a synchronized regulatory framework and a unified definition of NHPs in Canada, accomplished through consultations with industry representatives and policymakers, has facilitated bilateral communication to allow for the refinement of existing regulations [29]. The inclusion of multiple perspectives in the discussion also aided in clearly defining product categories and could serve as a resource for other jurisdictions planning to implement NHP regulation as a part of their established regulatory frameworks [29].

Theme 3: collaboration between various stakeholders (experts, policymakers, representatives of regulatory bodies, product companies, and research institutions) facilitating DHS regulation
Collaboration among stakeholder groups through committee meetings, workshops, and the creation of expert        is an area of concern for the United States which currently has rigorous lab and data accuracy measures compared to the European Union and Brazil.
Presence of varied universal regulatory assessments and policies. This causes a restriction in regard to judging and implementing a robust HM policy system in Brazil. Thereby, some products that are "harmless" could be deemed as irregular or unsafe and will be excluded from accepted HMs in novel policies (implying decreased variety for consumers).    The questionnaire constituted three different stages. The first component asked details about the representatives and information on general aspects of the company . The second module gathered information pertaining to any challenges faced during any of the following stages of raw material acquisition to marketing of the products and quality control procedures. The final part evaluated the export and import processes (submission requirements, review of timelines and its appropriateness, and support required from the government). Details from other organizations displaying good notions about Indian manufacturing companies were also noted. Data in the context of India's GMP regulation and legislative procedures for HMs were also examined.
A questionnaire was used to gather information on challenges faced during production, commercialization, and marketing approval of HMs in as over 60% of participants indicated that additional quality control proceedings should be developed. Devising harmonized regulations, and defined timelines, will assist in reducing the number of errors and outliers in the context of state-licensing laws. Not only will this remedy problems like product contamination, but also resolve issues such as substitution. The survey conducted unveiled how regulatory compliance remains the number one challenge for exporters. Like many other countries, the inconsistency in GMP is outlined as the primary impediments for Indian manufacturers. Conflicting regulatory procedures worldwide and application delays were another area of concern. Worldwide variability in herbal medicine approval process: loose laws in India, whereas in the European Union it needs to successfully pass through a full regimen, requiring exhaustive safety and efficacy data. In addition, there exists a scarcity of herbal practitioners. Drug manufacturers are not able to keep up with increasing standards for herbal medicinal products. There also exists inadequate research and development, and slow pace of modernization.   [29] 15 key informants were interviewed, including government representatives (n = 5), industry Data were collected from semi-structured interviews with key informants, using ten questions. They were also asked about any relevant documents and additional stakeholders that could contribute to this study. Field notes were taken and analyzed, and along with the interview tapes and transcripts, recurring issues and data patterns were identified.
Sixteen semi-structured interviews with stakeholders of the Lebanese complementary and alternative medicine market, and these interviews were transcribed. The scripts were analyzed for any emerging themes, identified through recurring issues and patterns that were arisen from the data.   committees may help in developing effective regulatory policies for DHSs. The Nigerian government concluded that there was a need for collaboration with global partners, specifically the World Health Organization that has developed programs to foster information sharing about regulatory issues such as the lack of research data, appropriate mechanisms for the control of HM, expertise within the health authorities and control agencies, and monitoring of consumer safety at international workshops. In this way, Nigeria could build its national capacity on establishing HM regulations [7]. In a study conducted in Kuwait, managers working in the registration of HMs and scientific reviewers performing quality assessments of HMs found that the increased cooperation between government officials in the National Health Regulatory Authority and the Saudi Food and Drug Authority was crucial in addressing the need to introduce an HM classification policy. Committee meetings between Kuwaiti government officials and external experts were seen as opportunities for sharing ideas, knowledge, and expertise. Consequently, clear objectives and realistic timelines for developing effective regulatory policies and guidelines for the classification of HM products were established [18]. Moreover, regular meetings between scientific reviewers and senior managers involved in the HM product registration process allowed the two stakeholder groups to decide whether to register particular products under the traditional herbal medicine registration pathway, resulting in a smoother classification process [18].
In Namibia, the forum Devil's Claw Working Group was established to facilitate policy development for devil's claw (Harpagophytum spp.). In collaboration with the Ministry of Environment and Tourism-Directorate of Natural Resource Management, this forum has hosted international consultations and workshops for the review and harmonization of devil's claw's regulatory policies [9]. Working groups in the Southern Africa region were also established for the facilitation of information exchange and joint learning practices of INPs between South Africa, Botswana, and Namibia [9]. Likewise, Nigeria has recognized the importance of having expert committees review HMs and has established a Scientific Committee on Verification of Herbal Medicine to ensure the safety, efficacy, and quality of these products [7]. In creating this committee, the Federal Ministry of Health focused on increasing collaboration among stakeholders and ensuring effective implementation of Nigerian regulations for the safe use of HMs. Similarly, in Canada, communication and consultation sessions are held annually by the Natural Health Product Directorate Advisory Committee to allow for the exchange of feedback regarding NHP regulations between stakeholder groups and the subsequent refinement of policies and product categories [29,31].
Furthermore, the lack of contact between Brazilian HM product companies and national research centers resulted in insufficient university research and information on the development or licensing of HMs before receiving marketing approval [32]. Therefore, the National Health Surveillance Agency of Brazil (ANVISA), which oversees the licensing and health surveillance of HM products, has recognized the importance of knowledge mobilization and active collaboration between the HM researchers and regulators, and thus has engaged in various cooperative initiatives. Most notably, the International Pharmaceutical Regulators Forum encourages coordination between countries such as the United States, Canada, and India for the exchange of information gathered from research investigations, which may help to strengthen existing research on HM regulations in other countries [33]. ANVISA has even proposed organizing regular meetings with the Food and Drug Administration (FDA) to share information on regulatory policies regularly [33,34].

Summary of findings
The purpose of this scoping review was to identify the facilitators and barriers to DHS regulations internationally. Our systematic search yielded 15 articles that met our eligibility criteria and were included for data extraction. Our analysis identified three main themes: (1) increased financial and human resources encouraging knowledge expansion as a facilitator to DHS regulation; (2) variances in DHS classification and regulatory requirements across countries as a barrier to DHS regulation; and (3) collaboration between various stakeholders (experts, policymakers, representatives of regulatory bodies, product companies and research institutions) facilitating DHS regulation. To our knowledge, this is the first study to systematically evaluate and summarize facilitators and barriers to DHS regulatory frameworks globally; our findings may provide policymakers, healthcare professionals, and other stakeholders with insight into what specific factors affect DHS regulation.

Unique challenges associated with DHS regulation
DHSs have generally lacked well-developed regulatory frameworks when compared to that of pharmaceuticals and medical devices, resulting in a variety of unique challenges. In the United States, DHSs can be sold and marketed around the world without providing the FDA with evidence of the product's safety and efficacy, as mandated by the Dietary Supplement Health and Education Act [35]. A meta-analysis of 26 high-quality systematic reviews reported that DHSs were commonly contaminated with dust, pollen, and/or toxic heavy metals that could cause severe adverse effects, such as multi-organ failure and lead or mercury poisoning [36]. Furthermore, safety risks of raw herbal materials require attention as western countries such as Australia lack regulations for their imported materials, especially from China [37]. Specifically, the regulation of restricted and contaminated substances conducted by Customs and Quarantine control, a department managed by the Australian Department of Home Affairs, has insufficiently conducted appropriate quality control procedures that should be performed to detect any contamination or pollution of these substances, which may include the use of mass spectrometry and chemical fingerprinting [38]. Moreover, due to the lack of a clear classification system in Kuwait, some DHSs have been registered under the unclassified unit as dietary supplements, which has fewer stringent requirements for registration. As a result, some products are marketed inappropriately, presenting health and safety issues to the public [7]. Additionally, although guidelines have been drafted for the preclinical safety evaluations of Ayurveda, Siddha, and Unani within the Indian DHS registration system, there are currently no regulatory policies for the standardization of herbal preparation and marker-based identification of active components, which could lead to adulteration, misidentification, mislabelling, and contamination of DHSs [24,39]. In contrast, there have been initiatives to improve existing regulations and to help mitigate these safety concerns elsewhere. For example, the Committee on Herbal Medicinal Products in the European Union was established to harmonize the regulation of HMs and facilitate its marketing [40]. The European Pharmacopeia was developed to provide a system of complete technical standards and requirements for the regulation and application of HMs in the European Union market, creating a standard for the safety and efficacy evaluation of DHSs [41]. In addition to the inherently complex nature of DHSs, adverse effects reported by consumers have been linked to deviations from good manufacturing practices (GMP), intentional substitutions and adulterations from the use of cheaper components, and improper preparations and dosages [42,43]. In an effort to raise standards of safety and quality, inspections of DHS manufacturing facilities are being conducted under the GMP, which is overseen by regulatory agencies such as the Center for Drug Evaluation and Research in the United Kingdom, United States, Canada, the European Union, China, and India [43]. It is difficult for manufacturing companies to correctly identify plant parts and starting materials of DHSs when complying with GMP due to the high phenotypic variation between similar plant products, unidentifiable plant extracts, and the lack of highly trained professionals in plant taxonomy that leads to mistaking one herb for another due to their similar appearances or incorrect labeling [44,45]. Therefore, the World Health Organization has recommended implementing national quality specification measures and standards, GMP, labeling, and licensing schemes for manufacturing in countries where DHSs are regulated [45]. Furthermore, the classification of herbal medications as dietary supplements under the United States Dietary Supplement Health and Education Act allowed DHSs to be marketed without providing proof of safety and efficacy, instead shifting the responsibility of blocking the marketing of unsafe dietary supplements to the FDA which remains understaffed and underfunded to fully enforce these rules [46]. These relaxed regulations have benefited manufacturers, as being subject to many legal requirements is often challenging and counterproductive to the production process [47]. There has even been a divide between regulators and manufacturers with regard to quality testing of DHSs, as manufacturers are hesitant about requiring stricter analytical methods for DHS ingredients due to the significant expertise and monetary costs that are involved [35]. In fact, conducting clinical trials to demonstrate a new pharmaceutical's safety and efficacy in the United States was estimated to cost $500 million, which is uneconomical for the private industry of DHSs [48]. Namely, unlike pharmaceuticals, DHSs cannot be patented, causing manufacturers to face price pressure from their competitors and thus lack the profits to fund such costly clinical trials [49].

Future areas of research
The differences in DHS classification guidelines and definitions between drug regulatory authorities is one of the primary factors that have made it difficult for countries such as Brazil and Kuwait to regulate these products consistently over time. For instance, DHSs with the same ingredients have been placed under multiple categories that have different requirements of safety and efficacy evaluation due to a variety of registration applications being processed for similar products [18]. Science-based quality standards, such as the up-to-date standards, may help to set appropriate quality attributes of DHSs between manufacturers, regulators, and other stakeholders when assessing their ingredients to ultimately homogenize the requirements, definition, and terminology of its categorization [50,51]. Additionally, emerging technologies such as DNA barcoding and nextgeneration sequencing can help to identify the origin of products, discriminate between similar species, and ensure reproducible results, thus improving research to establish a common reference standard between agencies [52]. Surveillance systems, such as China's Adverse Drug Reaction Monitoring System and the FDA's Med-Watch program, have also provided important information regarding adverse events associated with DHSs [52]. Further to this, 4 out of the 11 countries in South-East Asia have established national systems for monitoring the safety of DHSs. Hence, it has been suggested that a global surveillance system be established to assist with the identification of product origin and to communicate precise product characteristics [43]. The establishment of national safety monitoring programs for DHSs may facilitate the collection and analysis of reports of adverse effects from consumers of these products and subsequently aid in informing regulatory authorities of the appropriate safety and efficacy requirements.

Strengths and limitations
A notable strength of this study includes the use of a systematic search strategy to identify the studies included in this review. Interpretation of these findings was strengthened by the fact that two authors (MK and AS) independently screened, extracted data, summarized findings, and met with the supervising author (JYN) to resolve any discrepancies. Limitations of this review include the exclusion of non-English language articles, potentially omitting studies that emerge from non-English speaking countries. Furthermore, a small number of articles were irretrievable, despite receiving assistance from our university librarian in placing interlibrary loan requests. We also did not include a search of the grey literature and acknowledge that this review may not necessarily capture industry researchers' evaluations of global DHS regulatory frameworks; however, this is justified considering the parameters of our research question, which was to assess DHS regulations specifically and identify only research in the peer-reviewed literature.

Conclusion
The present scoping review systematically searched the literature to identify facilitators and barriers to DHS regulation across different countries while also highlighting several important themes. Our findings suggest that the adoption of a harmonized regulatory system could help to ensure that products are evaluated with the most appropriate conformity assessments, and that government financial and human resource incentives could promote the conducting of more ethically sound international DHS research. Furthermore, a greater degree of collaboration between stakeholders could encourage increased resource mobilization, the development of knowledge exchange initiatives, and the establishment of feedback opportunities to improve regulations. We also highlight that safety assessments of DHSs continue to be inadequate, and emerging technologies could potentially play a significant role in establishing common reference standards of herbal materials and products between regulatory agencies. Finally, we believe that regulatory harmonization, increased scientific research, and greater collaboration could improve regulations globally by ensuring appropriate categorization and safe application of DHSs.